Mammary duct luminal epithelium controls adipocyte thermogenic programme

Sanil Patel, Njeri Z. R. Sparman, Douglas Arneson, Alexandra Alvarsson, Luís C. Santos, Samuel J. Duesman, Alessia Centonze, Ephraim Hathaway, In Sook Ahn, Graciel Diamante, Ingrid Cely, Chung Hwan Cho, Noble Kumar Talari, Abha K. Rajbhandari, Leigh Goedeke, Peng Wang, Atul J. Butte, Cédric Blanpain, Karthickeyan Chella Krishnan, Aldons J. Lusis, Sarah A. Stanley, Xia Yang and Prashant Rajbhandari ()
Additional contact information
Sanil Patel: Icahn School of Medicine at Mount Sinai
Njeri Z. R. Sparman: Icahn School of Medicine at Mount Sinai
Douglas Arneson: University of California
Alexandra Alvarsson: Icahn School of Medicine at Mount Sinai
Luís C. Santos: Icahn School of Medicine at Mount Sinai
Samuel J. Duesman: Icahn School of Medicine at Mount Sinai
Alessia Centonze: Université Libre de Bruxelles (ULB)
Ephraim Hathaway: Icahn School of Medicine at Mount Sinai
In Sook Ahn: University of California
Graciel Diamante: University of California
Ingrid Cely: University of California
Chung Hwan Cho: Icahn School of Medicine at Mount Sinai
Noble Kumar Talari: University of Cincinnati College of Medicine
Abha K. Rajbhandari: Icahn School of Medicine at Mount Sinai
Leigh Goedeke: Icahn School of Medicine at Mount Sinai
Peng Wang: Icahn School of Medicine at Mount Sinai
Atul J. Butte: University of California
Cédric Blanpain: Université Libre de Bruxelles (ULB)
Karthickeyan Chella Krishnan: University of Cincinnati College of Medicine
Aldons J. Lusis: University of California
Sarah A. Stanley: Icahn School of Medicine at Mount Sinai
Xia Yang: University of California
Prashant Rajbhandari: Icahn School of Medicine at Mount Sinai

Nature, 2023, vol. 620, issue 7972, 192-199

Abstract: Abstract Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2–7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors ‘mammokines’. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve–ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.

Date: 2023
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DOI: 10.1038/s41586-023-06361-5

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